4-hydroxybutyl,6-hydroxyhexyl and 8-hydroxy-octyl prostaglandin esters

ABSTRACT

Prostaglandin esters are prepared by converting prostanoic acid into tertiary amine salts, reacting the salts with an alkylsulfonyl halide or phenylsulfonyl halide to form a mixed acid anhydride of carboxylic acid and sulphonic acid. The anhydride is then reacted with an alcohol to form prostaglandin esters.

United States Patent [191 Kurono et al.

4-HYDROXYBUTYL, 6-HYDROXYHEXYL AND S-HYDROXY- OCTYL PROSTAGLANDIN ESTERS Inventors: Masayasu Kurono, Osaka; Fusae Komoto, Kyoto; Takeshi Chiba; Masaki Hayashi, both of Takatsuki, all of Japan Assignee: Ono Pharmaceutical Co., Ltd.

Filed: Nov. 11, 1971 Appl. No.: 197,930

Foreign Application Priority Data Dec. 7, I970 Japan 45-l0829l.

US. Cl...... 260/468 D, 260/514 D, 260/240 R, 260/545 R, 260/295 S, 260/295 R, 260/326 Int. Cl. C07c 69/74 Field of Search 260/468 D, 514 D References Cited UNITED STATES PATENTS 8/197 Bergstrom et al. 260/468 D OTHER PUBLICATIONS Organic Synthesis-Migrdichian (1957), Vol. I, Pages 323-325, Reinhold PublishingtCorp.

Kirk-0thmer, Encyclopedia of Chemical Technology 2nd Ed., Vol. 8, (1965), page 335.

Primary Examiner-John D. Randolph Assistant Examiner-S. D. Winters Attorney, Agent, or Firm-Bierman & Bierman Prostaglandin esters are prepared by converting pros- ABSTRACT tanoic acid into tertiary amine salts, reacting the salts with an alkylsulfonyl halide or phenylsulfonyl halide to form, a mixed acid anhydride of carboxylic acid and sulphonic acid. The anhydride is then reacted with an alcohol to form prostaglandin esters.

13 Claims, No Drawings 4-HYDROXYBUTYL, 6-HYDROXYHEXYL AND S-HYDROXY- ()CTYL PROSTAGLANDIN ESTERS This invention relates to a process for producing prostaglandin esters.

Prostaglandins occur or exist in various tissues of animals and are secreted within living bodies, and are known as new hormones which act, even in a slight amount, on smooth nucleus, blood pressures and lipid metabolisms or the like.

It has already been proposed to produce esters of prostaglandins by reacting a diazo alkyl with a prostaglandin (Japanese Patent Application No. 44-70140/69) of by using dicyclohexyl carbodiimide (Japanese Patent Application No. 45-64911/70). However, in such processes, it is difficult to produce an ester of an alcohol containing a nitrogen atom, an alcohol containing a hydroxyl group which is easily sub;

jected to intermolecular dehydration, or an alcohol having a steric hindrance. j

We have now found an improved and economical method for producing prostaglandin esters which can be effectively carried out regardless of the structure of the alcohol.

Thus according to this invention there is provided a process for producing prostaglandin esters character ised by converting a prostaglandin into its tertiary amine salt, reacting said salt with an alkylsulfonyl halide or phenylsulfonyl halide to form a mixed acid anhydride of carboxylic acid and sulfonic acid, and then reacting said anhydride with an alcohol.

As for the prostaglandin, any of prostaglandin E,, prostaglandin E prostaglandin F prostaglandin A and and prostaglandin A may. be used. 7

Thus the reactions of this invention may be represented by the following formulae depending upon the respective prostaglandins used.

Prostaglandin E Prostaglandin E \J CH2) c0011 (l) Tertiary amine C H Y (2) nso x n (($1 c v o S\- R 'R'-OH -9 Prostaglandin F (CH2)3COOH (l) Tertiary amine (2) RSOZX" In the above formulae, RSO X represents an alkylsulfonyl halide or phenylsulfonyl halide, and R'OH represents an alkyl alcohol, substituted alkyl alcohol or polyhydric alcohol.

In carrying out the process of this invention, a prostaglandin is dissolved in an excess of an alcohol or in a solution of an excess of an alcohol dissolved in a proper organic solvent. While stirring the solution at the room temperature or under cooling with ice, a tertiary amine is added thereto. After a few minutes, an alkylsulfonyl halide or phenylsulfonyl halide is added to the mixture. Then the solution is stirred at the room temperature for about 5 minutes to 1 hour.

After the termination of the reaction, the reaction mixture is washed with water, and then the organic layer is concentrated under reduced pressure to obtain crude product, which is separated and purified by column chromatography on silica gel.

The organic solvent may be any suitable one which does not participate in the reaction, such as methylene chloride, ether or chloroform.

As for the tertinary amine it is preferable to employ trimethylamine, triethylamine, tributylamine, trioctylamine, pyridine or the like.

It is preferable that the amount of the tertiary amine is equal or in a small excess of2 equivalents to the prostaglandin used.

The amount of the alcohol to be added may be 1 to 50 mols per mol of the prostaglandin. The amount of the sulfonyl halide may be equivalent to or in a small excess of one equivalent to the prostaglandin used.

As for the alcohols there may be used various compounds because, as explained before, the process of this invention can be effectively proceeded regardless of the chemical structure of the alcohol. Thus, alkyl alcohols, substituted alkyl alcohols and polyhydric alcohols may be used.

Examples of alkyl alcohols are straight chained or branched alcohols or cycloalkyl alcohols having up to 14 carbon atoms, e.g. methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, amyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, nonyl alcohol, dccyl alcohol, dodecyl alcohol, tetradecyl alcohol, isopropyl alcohol, isobutyl alcohol, t-butyl alcohol, isoamyl alcohol, neopentyl alcohol, 2-ethyl butyl alcohol, Z-ethyl 8 ll 10 o o s R O R'OH hexyl alcohol, cyclopentaonol, cyclohexanol, cyclohexyl methyl alcohol, B-cyclohexyl ethyl alcohol, etc.

As for substituted alkyl alcohols, there may be used alkyl alcohols substituted with aromatic or functional groups containing nitrogen, oxygen, halogen, etc. More particular examples thereof are benzyl alcohol, B-phenyl ethyl alcohol, a-phenyl ethyl alcohol, 3- phenyl propyl alcohol, cinnamyl alcohol, diethylaminoethyl alcohol, dimethyl amino ethyl alcohol, 2- pyridyl methyl alcohol, 3-pyridyl methyl alcohol, 2- phthalimido ethyl alcohol, 2-propoxy ethyl alcohol, 2- phenoxy ethyl alcohol, tetrahydro furfuryl alcohol, piperonyl alcohol, 8-carbethoxyl octyl alcohol, 9- carboethoxy nonyl alcohol, ll-carboethoxy undecyl alcohol, cholesterol, 2,2,3,3,4,4,5,5-octafluoro-lpentyl alcohol, etc.

Examples of polyhydric alcohols which may be used I are ethylene glycol, propylene glycol, l,'4butane glycol, 1,6-hexane glycol, 1,8-octane dihydroxy naphthalene, glycerol, etc.

The .sulfonyl halide to be used in this invention is represented by the formula:

RSO X -carboethoxyl wherein R is a member selected from the group consisting of lower alkyl radicals (e.g. methyl and ethyl) and phenyl radicals substituted or not with lower alkyl radicals, and X is a halogen atom (e.g chlorine, bromine, etc.).

The process of this invention is applicable to the production of known prostaglandin esters. Further, according to this invention, there can be produced various novel prostaglandin esters which are, for example, as follows:

Prostaglandin E,-n-decyl ester,

Prostaglandin E -tetrahydrofurfuryl ester,

Prostaglandin F -9-carboethoxynonyl ester,

Prostaglandin A -2-diethylaminoethyl ester,

Prostaglandin E -2-pr0poxyethyl ester,

Prostaglandin E -2-phenoxyethyl ester,

Prostaglandin E -2dimethylaminoethyl ester,

Prostaglandin E -2-dicthylaminocthyl ester,

Prostaglandin E -2-phthalimidylethyl ester,

Prostaglandin E -piperonyl ester,

glycol, 1,5-

Prostaglandin E -Z-pyridyl methyl ester,

Prostaglandin E -3-pyridyl methyl ester,

Prostaglandin E -4-hydroxy butyl ester,

Prostaglandin E -6-hydroxy hexyl ester,

Prostaglandin E -8-hydroxy octyl ester,

Prostaglandin E -glycerol monoester,

Prostaglandin E '8-carboethoxyoctyl ester,

Prostaglandin E -9-carboethoxynonyl ester,

Prostaglandin E -1 l-carboethoxyundecyl ester,

Prostaglandin E -tetrahydrofurfuryl ester,

Prostaglandin E cholesterd ester,

Prost'aglandin A -2-dimethylaminoethyl ester,

Prostaglandin A -2-dimethylaminoethyl ester,

Prostaglandin A -4-hydroxybutyl ester,

Prostaglandin A -6-hydroxyhexyl ester, and

Prostaglandin. A -8-hydroxyocty1 ester.

Upon conducting screening tests of inhibiting effect on histamine-induced asthma of theprostaglandin esters of this invention, it has been found that these esters have excellent inhibiting effects.

Thus, for example, when a screening test of protective drugs for experimental asthema of animals as re- I ported by Iwasawa et al. (Folia Pharmacologica J aponica 63 28 41 (1967) was conducted, it was foundthat each of Z-diethylaminoethyl ester, 8-carboethoxyoctyl ester and 9-carboethoxy nonyl ester of prostaglandin E is more than 10 and 7 times as effective as, respectively, isoproterenol and prostaglandin E used as control drugs.

Further, when each of such esters as 4-hydroxybutyl ester, 6-hydroxyhexyl ester, 8-hydroxyoctyl ester and tetrahydrofurfuryl ester of this invention was injected intravenously into a barbital-anes-thetized dog, it has been found that its hypotensive effect is much superior to that of prostaglandin E The above results indicate that the prostaglandin esters of this invention have a clinically significant value.

The invention will be further explained by referring to the following Examples which are given for the illustration purpose only and not for limiting the scope of this invention.

Example 1 56.3 mg. of prostaglandin E 35.5 mg. of triethyl amine and 0.4 ml. of n-decyl alcohol were dissolved in 1 ml. of dry methylene chloride. After the solution was stirred for 5 minutes, 33.7 mg. of paramethylbenzolsulfonyl chloride was added. The mixture was further stirred at the room temperature for 'minutes. The reaction solution was diluted with 50 ml. of cyclohexane and purified by Column-chromatography on 10 g. of silica gel. First, the by-product and alcohol were eluted and removed with a mixture of cyclohexane and ethyl acetate (4:1 Then eluting with a mixture of cyclohexane and ethyl acetate (3:2), 53.5 mg. of protstaglandin E -n-decyl ester was obtained in a 68.0 percent yield. Colorless crystals. Infrared absorptions (neat) were at 3320 (hydroxyl group), 2920, 2850, 1740 (ester, ketone), 1470 and 970 cm.

Elemental analysis:

Calculated 7 Found 7 Example 2 for 5 minutes, 35.4 mg. of benzolsulfonyl bromide was added to the solution. The mixture was further stirred at the room temperature for 30 minutes. Then 50 ml. of ethyl acetate was added to the reaction solution and the reaction solution was washed with water. The ethyl acetate layer was separated and drived over sodium sulfate and then concentrated under reduced pressure. The obtained concentrated residue was purified by column chromatography on silica gel. The product was eluted with mixtures of cyclohexane and ethyl acetate first at a ratio of 2:1 and then at a ratio of 1:1 to obtain 25.6 mg. of prostaglandin E -tetrahydrofurfuryl ester in a 40.2 percent yield. Colorless oily substance. Infrared absorptions (neat) were at 3400 (hydroxyl group), 2930, 2860, 1740 (ester, ketone). 1460, 1250, 1160, 1085 and 970 cm".

Elemental analysis:

' C H Calculated 68.77 2 9.24 '11 Found 68.54 7? 9.39 '71 1 Example 3 32.1 mg. of'prostaglandin F 20.2 mg. of triethylamine and 0.3 ml. of 9carboethoxynonyl alcohol were dissolved in 1 ml. of dry methylene chloride. After stirring for 5 minutes, 17.7 mg. of benzolsulfonyl chloride was added to the solution. The mixture was further stirred at the room temperature for 30 minutes. Then the reaction solution was diluted with 50 ml. of cyclohexane and purified by column-chromatography on 10 g. of silica gel. The byproduct and alcohol were eluted and removed with mixtures of cyclohexane and ethyl C t H Calculated 69.53 10.21 7: Found 69.66 72 10.42 7:

Example 4 34.5 mg. of prostaglandin A 23.0 mg. of triethylaminc and 0.2 ml. of diethylaminoethanol were dissolved in 1 m1. of dry methylene chloride. After stirring for 5 minutes, 20.2 mg. of benzolsulfonyl chloride was added to the solution. The mixture was further stirred at the room temperature for 30 minutes. Then 25 ml. of ethyl acetate was added to the reaction solution and the reaction solution was washed with water. The ethyl acetate layer was separated and dried over sodium sulfate and then concentrated under reduced pressure. The obtained concentrated residue was purified by columnchromatography on 5 g. of silica gel. The product was eluted with ethyl acetate to obtain 30.0 mg. of prostaglandin A -2-diethylaminoethyl ester in a 67.3 percent yield. Yellow oily product. Infrared absorptions (chloroform solution) were at 3400 (hydroxy group), 2920, 2850, 1725 (ester), 1700 (ketone), 1585, 1450, 1170 and 970 cm".

Elemental analysis:

Calculated 7 Found 7 tained.

4 Elemental anal sis Prostaglandm E ester Appearance Infrared absorption (cm") Calculated Found C(%) H(%) C(%) H(%) Colorless 3400, 2920, 2850, 1740, 1240. 2-propoxyethyl ester oily 1160. 1130, 970 68.46 9.65 68.28 9.79

3380, 2920, 2850, 1740, 1600. 2-phenoxyethyl Colorless 1500. 1250. 1160, 1080, 970, 71.16 8.53 71.22 8.73 ester crystalline 760, 695

A 3400, 2920, 2850, 2760, 1735, 2-dimethylamlno- Yellow 1460, 1375, 1240, 1160, 1080, 68.05 9.76 68.23 9.8 ethyl ester oily 970 (3 31 N) (3.20 N) 2diethy1ammo- Yellow 3400, 2920, 2850, 1735. 1460, 69.14 10.04 9.26 10.30 ethyl ester oily 1375, 1240, 1160, 1070, 970 (3.10 N) (2.86 7: N)

3450, 3400, 2920, 2850. 1775, 2-phthalimidyl- Yellow 1740, 1710, 1430, 1395, 1240, 68.55 7.48 68.45 7.56 ethyl ester oily 1160. 1080. 970 (2.67 N) (2.77 N) 3380, 2920, 2850, 1740, 1500, Piperonyl ester Colorless 1440, 1240, 1150, 1040, 970, 69.11 7.87 69.32 7.98

oily 925 Tetrahydrofurfuryl Colorless 3400. 2930, 2860, 1740, 1460, 68.77 9.24 68.54 9.39 ester oily 1250, 1160, 1985. 970 2-pyridylmethyl Yellow 3380, 2920. 2850, 1735. 1595, 70.40 8.41 70.28 8.64 ester oily 1435, 1240, 1155,1080. 970 (3.16 7? N) (3.36 71 N) 3 pyridylmethyl Yellow 3360. 2920. 2850. 1735, 1600. 70.40 8.41 70.48 8.39 ester oily 1425. 1240.1155. 1080. 970 (3.16 7: N) (3.28 '71 N) 4-hydroxybuty1 Colorless 3380, 2920. 2850. 1735. 1245, 67.89 9.50 67.63 9.46 ester 0' 1160. 1070. 970 o'hydroxyhcxyl Colorless 3380. 2920. 2850. 1740. 1460. 68.99 9.80 69.03 9.68 ester crystalline 1245, 1160, 1080, 970 tl-hydroxyoctyl Colorless 3380. 2920, 2850. 1740, 1460, 69.96 10.07 69.73 10.31 ester crystalline 1245, 1160, 1080. 970 Glycerol mono- Yellow 3380. 2920. 2850. 1740. 1450, 64.76 8.98 64.51 8.99 ester oily 1245. 1160, 1070.970 8carboethoxy- Colorless 3400. 2920. 2850. 1735, 1460, 69.37 9.77 69.20 9.94 octyl ester crystalline 1245, 1160, 1070. 970 9-carboethoxy- Colorless 3400, 2920. 2850, 1730. 1460. 69.78 9.88 69.93 9.92 nonyl ester oily 1240. 1180, 1080.970 llcarboethoxy Colorless 3400. 2920, 2850, 1735. 1460, 70.55 10.10 70.37 10.28 undecyl ester crystalline 1245, 1160, 1070, 970 Prostaglandin E ester ndeeyl ester Colorless 3320, 2920, 2850, 1740, 1470, 72.83 10.99 72.71 11.06

- crystalline 970 Tetrahydrofurfuryl Colorless 3380, 2920, 2850, 1730, 1450, 68.46 9.65 68.44 9.72 ester oily 1230, 1160, 1080.970 Cholesterol ester Colorless 3370, 2920, 2850, 1735, 1460, 78.06 10.87 78.32 10.94

' oily 1380, 1170, 1070.970 Prostaglandin F ester 9-carboethoxynonyl Colorless 3400, 2920, 2850, 1725. 1460, 69.53 10.21 69.66 10.42 ester oily 1240, 1180. 970 Prostaglandin A, ester 2-dimethy1amino- Yellow 3450, 2920, 2850, 2760. 1735. 70.72 10.14 70.66 10.38 ethyl ester oily 1710, 1585, 1460,1180, 970 (3.44 7: N) (3.21% N) Prostaglandin A ester Z-dimethylamino- Yellow 3400, 2920, 2850. 2760,1725, 71.07 9.69 70.98 9.83 ethyl ester oily 1700, 1585, 1450. 1170.970 (3 45 7! N) (3.56 71 N) 2-diethylamino- Yellow 3400, 2920. 2850, 1725, 1700, 72.01 10.00 72.26 10.08 ethyl ester oily 1585. 1450, 1170.970 (3.23 7: N) (3.09 Z N) 4-hydroxybutyl Colorless 3400, 2920. 2850, 1720. 1700. 70.90 9.42 71.13 9.44 ester oily 1585, 1450, 1180. 975 6hydroxyhexyl Colorless 3420, 2920, 2850, 1720, 1700, 71.85 9.74 71.78 9.92 ester oily 1585. 1450. 1180.975 8-hydroxyoctyl Colorless 3400. 2920. 2850, 1720. 1 700, 72.69 10.02 72.90 10.09 ester oily 1585, 1450. 1180.975

What we claim is:

l. A prostanoic acid ester having the structure in which A is B is -CH=CH or CH -CH hydroxybutyl, 6-hydroxyhexyl, or 8-hydroxyoctyl.

2. The prostanoic acid ester of claim 1 in which A is and R is 4- 3 ,821,279 13 14 and B iS CH=CH- 9. The ester of claim 6 in which R is S-hydroxyoctyl.

3. The ester of claim 2 in which R is 4-hydroxybutyl.

4. The ester of claim 2 in which R is 6-hydroxyhexyl. is

5. The ester of claim 2 in which R is S-hydroxyoctyl. H 6. The prostanoic acid ester of claim 1 in which A is Q" and B is -CH=CH.

I 11. The ester of claim 10 in which R is 4- l5 hydroxybutyl.

and B is C 12. The ester of claim 10 in which R is 6- 7. The ester of claim 6 in which R is 4-hydr0xybutyl, h d hexyl.

13. The ester of claim 10 in which R is 8- 8. The ester of claim 6 in which R is 6-hydroxyhexyl. h d t L 10. The prostanoic acid ester of claim 1 in which A 

2. The prostanoic acid ester of claim 1 in which A is
 3. The ester of claim 2 in which R is 4-hydroxybutyl.
 4. The ester of claim 2 in which R is 6-hydroxyhexyl.
 5. The ester of claim 2 in which R is 8-hydroxyoctyl.
 6. The prostanoic acid ester of claim 1 in which A is
 7. The ester of claim 6 in which R is 4-hydroxybutyl.
 8. The ester of claim 6 in which R is 6-hydroxyhexyl.
 9. The ester of claim 6 in which R is 8-hydroxyoctyl.
 10. The prostanoic acid ester of claim 1 in which A is
 11. The ester of claim 10 in which R is 4-hydroxybutyl.
 12. The ester of claim 10 in which R is 6-hydroxyhexyl.
 13. The ester of claim 10 in which R is 8-hydroxyoctyl. 